Impact of Variant Reclassification: Insights from Greenwood Genetic Center
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Genetic testing is essential for diagnosing and treating patients, with variant classification being a critical component of this process. Variant reclassification can challenge diagnostic accuracy over time. This study aims to evaluate the impact of variant reclassification by analyzing data for reclassification requests received by the Greenwood Genetic Center (GGC) from external and internal institutions.
Methods:
A retrospective analysis was conducted on cases with variant reclassification requests at GGC between 2019 and 2024, including 258 variants of uncertain clinical significance (VUS). The analysis evaluated variant types, changes in pathogenicity, the criteria used for classification, and the time interval for reclassification.
Results:
Among the 258 VUS variants, 72% (186/258) remained VUS, 17.4% (45/258) were upgraded to pathogenic (P) or likely pathogenic (LP), and 10.5% (27/258) were downgraded to likely benign (LB) or benign (B). Of the variants reclassified as P/LP, 82.2% were missense variants, while the remaining variants included nonsense, frameshift, and intronic alterations.
Among 45 variants upgraded to P/LP, 82.2% (37/45) were missense variants, and the following ACMG criteria were applied: population data (PS4 with varying degrees, PM2), computational data (PS1 with varying degrees, PM5 with varying degree, and PP3), functional data (PP2, PS3 with varying degrees, and PM1), segregation (PP1), de novo status (PS2/PM6), and allelic data (PM3). The primary contributions came from population data, computational data, functional data, and de novo status. Notably, the six most influential criteria were PM2 (86.5%, 32/37), PP3 (72.9%, 27/37), PM1 (51.3%, 19/37), PP2 (43.2%, 16/37), PS3 with varying degree (40.5%, 15/37). PS2/PM6 contributed 29.7% (11/37), as did PM5 and PS4 with varying degrees, respectively.
A comprehensive analysis of 42 VUS variants requested in 2024 showed that the longest interval for reclassification requests was 14 years, the shortest was 0.3 years, and the average was 4.25 years. 65% (13/20) of cases received a diagnosis within five years through reclassification.
Conclusion:
This evolving process is creating uncertainty in point-of-care decision-making, driven by current evidence and evolving standards. Our data indicated that variant reclassification could be considered the first-tier approach for undiagnosed diseases before exploring other advanced technologies. Additional family studies can significantly enhance the success rate of VUS reclassification by providing de novo status and co-segregation data, which should be actively considered for patients with VUS. Follow-up reclassification is recommended within five years.
Genetic testing is essential for diagnosing and treating patients, with variant classification being a critical component of this process. Variant reclassification can challenge diagnostic accuracy over time. This study aims to evaluate the impact of variant reclassification by analyzing data for reclassification requests received by the Greenwood Genetic Center (GGC) from external and internal institutions.
Methods:
A retrospective analysis was conducted on cases with variant reclassification requests at GGC between 2019 and 2024, including 258 variants of uncertain clinical significance (VUS). The analysis evaluated variant types, changes in pathogenicity, the criteria used for classification, and the time interval for reclassification.
Results:
Among the 258 VUS variants, 72% (186/258) remained VUS, 17.4% (45/258) were upgraded to pathogenic (P) or likely pathogenic (LP), and 10.5% (27/258) were downgraded to likely benign (LB) or benign (B). Of the variants reclassified as P/LP, 82.2% were missense variants, while the remaining variants included nonsense, frameshift, and intronic alterations.
Among 45 variants upgraded to P/LP, 82.2% (37/45) were missense variants, and the following ACMG criteria were applied: population data (PS4 with varying degrees, PM2), computational data (PS1 with varying degrees, PM5 with varying degree, and PP3), functional data (PP2, PS3 with varying degrees, and PM1), segregation (PP1), de novo status (PS2/PM6), and allelic data (PM3). The primary contributions came from population data, computational data, functional data, and de novo status. Notably, the six most influential criteria were PM2 (86.5%, 32/37), PP3 (72.9%, 27/37), PM1 (51.3%, 19/37), PP2 (43.2%, 16/37), PS3 with varying degree (40.5%, 15/37). PS2/PM6 contributed 29.7% (11/37), as did PM5 and PS4 with varying degrees, respectively.
A comprehensive analysis of 42 VUS variants requested in 2024 showed that the longest interval for reclassification requests was 14 years, the shortest was 0.3 years, and the average was 4.25 years. 65% (13/20) of cases received a diagnosis within five years through reclassification.
Conclusion:
This evolving process is creating uncertainty in point-of-care decision-making, driven by current evidence and evolving standards. Our data indicated that variant reclassification could be considered the first-tier approach for undiagnosed diseases before exploring other advanced technologies. Additional family studies can significantly enhance the success rate of VUS reclassification by providing de novo status and co-segregation data, which should be actively considered for patients with VUS. Follow-up reclassification is recommended within five years.